A significant challenge in the application of clinical hyperthermia is achieving a prescribed temperature distribution throughout the tumor volume. Blood flow and patient tolerance are limiting factors. The goals of this project address alternatives to these limitations by: 1) using vasoactive drugs to reduce tumor blood flow, which could result in increased temperatures during hyperthermia, and 2) examining methods to acutely decrease tumor pH, which could result in enhanced thermocytotoxicity without raising temperatures. The greatest potential for application of these two strategies may lie in combining both simultaneously with hyperthermia. We will study the effects of ion channel blockers, vasoactive agents, and hyperthermia alone and in combination on tumor pH, blood flow, and metabolic status in canine patients with spontaneous tumors. We will use 31phosphorus magnetic resonance spectroscopy (31P MRS), interstitial pH electrodes, and Eppendorf pO2 microelectrodes to monitor physiologic changes. We feel canine patients provide the appropriate model because: l) the tumors are spontaneous versus transplanted, 2) the biology of the tumors is similar to humans, 3) the temperature distributions during hyperthermia are similar to those achieved in humans, and 4) methods developed and used in this project can be directly applied to human clinical trials. At Duke University Medical Center (DUMC), we have unique resources, such as the availability of tumor-bearing pet dogs, a dedicated research MR scanner, and an Eppendorf PO2 Histograph device, which allow us to serially monitor multiple tumor physiologic parameters in a relevant spontaneous tumor model. The studies proposed in this project should help us develop safe and practical strategies to enhance thermal sensitivity in solid tumors which ultimately could be incorporated into Projects I and III. Although we are concentrating on improving the efficacy of hyperthermia, much of the information we obtain in this project could be applicable to understanding spontaneous tumor physiology in general.